Medulloblastoma (MB) is the most common malignant childhood brain tumor. Even with aggressive therapy, many patients still die of their disease. Moreover, survivors suffer severe long-term side effects as a result of treatment, which are thought to result in large part from radiation-induced damage to the developing nervous system. Unlike other brain tumors, which infiltrate through the brain parenchyma, MB commonly spreads through the meninges that surround the brain and spinal cord, a phenomenon termed leptomeningeal metastasis (LM). We recently performed a high throughput drug screen to identify the polypeptide antibiotic actinomycin as a compound of interest for the treatment of MB. We developed methods to encapsulate actinomycin within biodegradable and biocompatible polymeric nanoparticles. We have also identified a peptide ligand capable of targeting receptors that are upregulated on both spinal cord vasculature and patient derived MB. Our preliminary data demonstrate that actinomycin delivered from nanoparticles is significantly more effective at treating intracranial MB than free drug when administered intravenously. Further, we demonstrate that nanoparticles administered directly to the cerebrospinal fluid (CSF) localize with malignant cells to slow the growth of LM. In this work, we will evaluate delivery strategies (presence of targeting ligand, route of administration) to optimize these new approaches in MB. Nanoparticles will be barcoded to fluoresce in distinct wavelengths, such that the cellular level distribution of both control and targeted nanoparticle formulations can be evaluated within a single subject to directly assess nanoparticle fate and drug action at the cellular level. We will test test these systems in patient derived and genetically engineered models of MB exhibiting LM. We hypothesize that improved, targeted nanoparticle delivery will enhance exposure of metastatic cells to drug, to improve therapeutic efficacy and reduce the radiation dose needed to achieve complete tumor therapy. To test this hypothesis, we will (1) track delivery of targeted nanoparticles to malignant cells in the brain and spinal cord; (2) evaluate delivery, activity, and toxicity of actinomycin; and (3) test efficacy of targeted therapies in combination with radiation. Our experimental approach has been designed to sequentially refine the design of drug-loaded nanoparticles to yield a better treatment for MB by directly addressing LM as a unique disease burden. We expect that the outcome of these studies will also yield new strategies for spinal cord targeted drug delivery that will be relevant to other disseminated cancers or neurological diseases affecting the spinal cord.